Selectins, particularly P-selectin, contribute to many inflammatory and thrombotic diseases, such as deep venous thrombosis (DVT), arthritis, asthma, psoriasis, and vasoocclusive crisis in sickle cell anemia. For example, patients with sickle cell anemia suffer vasoocclusive complications in which sickled red cells clump in small vessels blocking blood flow (ischemia) to downstream organs. This causes patients intense pain and repeated hospitalizations. It can also lead to progressive multi-organ dysfunction and premature death. Murine models of sickle cell anemia have been developed by introduction of transgenes for the human globin proteins, one of which has the mutation found in sickle cell anemia. These mice have sickled red cells and develop vasoocclusive complications. The adherence of sickle red blood cells (RBCs) to the vascular endothelium appears to contribute to vaso-occlusion observed in sickle cell disease. Using genetically-engineered mice as a model for human sickle cell disease it was shown that there is a selectin-dependent recruitment of leukocytes to inflamed microvessels, where they interact with sickled red cells. Sickle cell mice exposed to hypoxia followed by reoxygenation had higher leukocyte rolling and lower RBC velocities in small vessels compared to controls. Injection of an anti-P-selectin monoclonal antibody at the time of reoxygenation not only prevented the increase in these parameters, it also reduced leukocyte rolling and increased RBC velocities to levels that approached those in unchallenged control mice. This indicates that a reduction in leukocyte adhesion can be accomplished by preventing P-selectin activity, thereby resulting in improved microcirculatory blood flow.
P-selectin has also been implicated in other disease processes, such as tissue and organ damage associated with inflammation, e.g., ischemia-reperfusion injury. Thus, P-selectin is a target for intervention in human inflammatory and thrombotic diseases. Accordingly, there is a need for treatments that target P-selectin as a means of treating inflammatory and thrombotic diseases.